Beta-arrstins (beta arrestin1&2) are ubiquitous multifunctional scaffold proteins involved in G protein coupled receptor (GPCR) signaling. Evidence from model cells suggests that binding of beta-arrestins desensitizes activated GPCRs by blocking receptor G protein interaction. However, the functional role of beta-arrestins in beta-adrenergic receptor (beta-AR) desensitization and recycling in physiological contexts remains largely elusive. Here, we demonstrate that deficiency of beta-arrestin2 in mice (beta-arrestin2 KO) causes defects in cardiac contractile response to stimulation of both beta-AR subtypes. The reduced beta-AR responsiveness is not associated with alterations in the densities or ligand binding properties of these receptors, but is related to a marked increase in beta2-AR phosphorylation. This unexpected finding is in sharp contrast to the established paradigm that beta-arrestin2 promotes beta-AR desensitization, and argues against the hypothesis that reduction or deficiency of beta-arrestin2 should enhance beta-AR signaling efficiency. Importantly, adenoviral gene transfer of beta-arrstin2 is able to fully restore beta-AR mediated contractile response in cardiomyocytes from beta-arrestin2 KO mice, indicating that the defect of beta-AR contractile response is attributable to the deficiency of beta-arrestin2 rather that the gene knockout associated nonspecific adaptive changes. These results also suggest that beta-arrestin2 plays an essential role in beta-AR resensitiztion, but not in the receptor desensitization. This conclusion is corroborated by the fact that in the failing hearts from spontaneous hypertensive rats (SHR), the abundance of beta-arrestin2 is markedly decreased before the onset of heart failure, and that the downregulation of beta-arrestin2 is accompanied by overtly attenuated cardiac contractile response to either beta-AR subtype stimulation. These findings have revealed a previously unrecognized crucial role of beta-arrestin2 in catecholamine-mediated contractile support and a potential causal relation between downregulation of beta-arresin2 and the development of heart failure. Thus, our study might reveals novel causal factors and potential therapeutic targets of heart failure.